Crystalline forms of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-D][2]benzazepin-2-yl]amino}-2-methoxybenzoate

ABSTRACT

The present invention is directed to a compound of formula (I): 
                         
or a crystalline form thereof, or a solvate thereof; to a solid pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I), or a crystalline form thereof, or a solvate thereof, and at least one pharmaceutically acceptable carrier or diluent, and to the use of a compound of formula (I), or a crystalline form thereof, or a solvate thereof, for treating a patient suffering from, or subject to, a disease, disorder, or condition mediated by Aurora kinase, and methods related thereto.

PRIORITY CLAIM

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 61/306,047, filed Feb. 19, 2010 (pending), which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateof formula (I):

or a crystalline form thereof, or a solvate thereof.

The invention is also directed to a process for the synthesis ofcrystalline forms of formula (I). The invention is also directed to thepharmaceutical use of crystalline forms of formula (I) as an Aurorakinase inhibitor, solid pharmaceutical compositions comprising thecrystalline forms of the invention, and methods of making suchpharmaceutical compositions.

BACKGROUND OF THE INVENTION

According to the American Cancer Society, approximately 560,000Americans died from cancer during 2006, while 2007 brought an estimated12 million new cancer cases worldwide. Although medical advances haveimproved cancer survival rates, there is a continuing need for new andmore effective treatment.

Cancer is characterized by uncontrolled cell reproduction. Mitosis is astage in the cell cycle during which a series of complex events ensurethe fidelity of chromosome separation into two daughter cells. Severalcurrent cancer therapies, including the taxanes and vinca alkaloids, actto inhibit the mitotic machinery. Mitotic progression is largelyregulated by proteolysis and by phosphorylation events that are mediatedby mitotic kinases. Aurora kinase family members (e.g., Aurora A, AuroraB, Aurora C) regulate mitotic progression through modulation ofcentrosome separation, spindle dynamics, spindle assembly checkpoint,chromosome alignment, and cytokinesis (Dutertre et al., Oncogene, 21:6175 (2002)); Berdnik et al., Curr. Biol., 12: 640 (2002)).Overexpression and/or amplification of Aurora kinases have been linkedto oncogenesis in several tumor types including those of colon andbreast (Warner et al., Mol. Cancer Ther., 2: 589 (2003); Bischoff etal., EMBO, 17: 3062 (1998); Sen et al., Cancer Res., 94: 1320 (2002)).Moreover, Aurora kinase inhibition in tumor cells results in mitoticarrest and apoptosis, suggesting that these kinases are importanttargets for cancer therapy (Ditchfield, J. Cell Biol., 161: 267 (2003);Harrington et al., Nature Med., 1 (2004)). Given the central role ofmitosis in the progression of virtually all malignancies, inhibitors ofthe Aurora kinases are expected to have application across a broad rangeof human tumors.

WO 05/111039, U.S. Pat. No. 7,572,784, US Publication No. 2007/0185087,US Publication No. 2008/0045501, WO 08/063525, US Publication No.2008/0167292, and US Publication No. 2010/0310651 hereby incorporated byreference in their entirety, disclose compounds that inhibit Aurorakinase enzymes. For example, the compound4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid of formula (II):

is a small molecule inhibitor of Aurora kinase.

These applications additionally disclose methods for the preparation ofthese compounds, pharmaceutical compositions containing these compounds,and methods for the prophylaxis and therapy of diseases, disorders, orconditions associated with overexpression and/or amplification of Aurorakinases, including, but not limited to, cell proliferative disorderssuch as cancer.

Sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I) is described in WO 08/063525 and U.S. Ser. No. 08/0167292, hereinincorporated by reference in their entirety. These references describethe synthesis of the compound of formula (I), which results in a mixtureof crystalline forms, Form 1 and Form 2, of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate.These applications do not disclose other specific salts or crystallineforms of4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid (II).

The large-scale manufacturing of a pharmaceutical composition poses manychallenges to the chemist and chemical engineer. While many of thesechallenges relate to the handling of large quantities of reagents andcontrol of large-scale reactions, the handling of the final productposes special challenges linked to the nature of the final activeproduct itself. Not only must the product be prepared in high yield, bestable, and capable of ready isolation, the product must possessproperties that are suitable for the types of pharmaceuticalpreparations in which they are likely to be ultimately used. Thestability of the active ingredient of the pharmaceutical preparationmust be considered during each step of the manufacturing process,including the synthesis, isolation, bulk storage, pharmaceuticalformulation and long-term formulation. Each of these steps may beimpacted by various environmental conditions of temperature andhumidity.

The pharmaceutically active substance used to prepare the pharmaceuticalcompositions should be as pure as possible, and its stability onlong-term storage must be guaranteed under various environmentalconditions. These properties are absolutely essential to prevent theappearance of unintended degradation products in pharmaceuticalcompositions, which degradation products may be potentially toxic orresult simply in reducing the potency of the composition.

A primary concern for the manufacture of large-scale pharmaceuticalcompounds is that the active substance should have a stable crystallinemorphology to ensure consistent processing parameters and pharmaceuticalquality. If an unstable crystalline form is used, crystal morphology maychange during manufacture and/or storage resulting in quality controlproblems, and formulation irregularities. Such a change may affect thereproducibility of the manufacturing process and thus lead to finalformulations which do not meet the high quality and stringentrequirements imposed on formulations of pharmaceutical compositions. Inthis regard, it should be generally borne in mind that any change to thesolid state of a pharmaceutical composition which can improve itsphysical and chemical stability gives a significant advantage over lessstable forms of the same drug.

When a compound crystallizes from a solution or slurry, it maycrystallize with different spatial lattice arrangements, a propertyreferred to as “polymorphism.” Each of the crystal forms is a“polymorph.” While polymorphs of a given substance have the samechemical composition, they may differ from each other with respect toone or more physical properties, such as solubility and dissociation,true density, melting point, crystal shape, compaction behavior, flowproperties, and/or solid state stability.

As described generally above, the polymorphic behavior of drugs can beof great importance in pharmacy and pharmacology. The differences inphysical properties exhibited by polymorphs affect practical parameterssuch as storage stability, compressibility and density (important informulation and product manufacturing), and dissolution rates (animportant factor in determining bio-availability). Differences instability can result from changes in chemical reactivity (e.g.,differential oxidation, such that a dosage form discolors more rapidlywhen it is one polymorph than when it is another polymorph) ormechanical changes (e.g., tablets crumble on storage as a kineticallyfavored polymorph converts to thermodynamically more stable polymorph)or both (e.g., tablets of one polymorph are more susceptible tobreakdown at high humidity). In addition, the physical properties of thecrystal may be important in processing: for example, one polymorph mightbe more likely to form solvates that cause the solid form to aggregateand increase the difficulty of solid handling, or might be difficult tofilter and wash free of impurities (i.e., particle shape and sizedistribution might be different between one polymorph relative toother).

While drug formulations having improved chemical and physical propertiesare desired, there is no predictable means for preparing new drug forms(e.g., polymorphs) of existing molecules for such formulations. Thesenew forms would provide consistency in physical properties over a rangeof environments common to manufacturing and composition usage. Moreparticularly, there is a need for an inhibitor of Aurora kinase,including in particular Aurora A or B. Such an inhibitor should haveutility in treating a patient suffering from or subject to Aurora kinasemediated pathological (diseases) conditions involving cell survival,proliferation and migration, including chronic inflammatoryproliferative disorders, e.g., psoriasis and rheumatoid arthritis;proliferative ocular disorders, e.g., diabetic retinopathy; benignproliferative disorders, e.g., hemangiomas; and cancer, as well ashaving properties suitable for large-scale manufacturing andformulation.

SUMMARY OF THE INVENTION

The present invention is directed to sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateof formula (I), or a crystalline form thereof, or a solvate thereof.These forms have properties that are useful for large-scalemanufacturing, pharmaceutical formulation, and storage. The presentinvention also provides solid pharmaceutical compositions comprisingsaid crystalline forms, and methods for uses of said crystalline forms,for the treatment of a variety of diseases, disorders or conditions asdescribed herein.

One embodiment of the invention is directed toward sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I), wherein the Sodium Salt is a single crystalline form; the possiblesingle crystalline forms being described herein.

Another embodiment of the invention is directed to a solidpharmaceutical composition comprising at least one pharmaceuticallyacceptable carrier or diluent; and sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I), wherein the Sodium Salt is a single crystalline form; the possiblesingle crystalline forms being described herein.

Another embodiment of the invention is directed to the use of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I), wherein the Sodium Salt is a single crystalline form; to prepare apharmaceutical composition, the possible single crystalline forms beingdescribed herein.

Other embodiments of the invention are directed toward methods oftreating a subject in need of an Aurora kinase inhibitor or a subjectwith cancer by administering an effective amount of a crystalline formof sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I), wherein the Sodium Salt is a single crystalline form; the possiblesingle crystalline forms being described herein.

Other embodiments of the invention are also directed to methods ofpreparing crystalline forms of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I), wherein the Sodium Salt is a single crystalline form, the possiblesingle crystalline forms being described herein.

The present invention shall be more fully discussed with the aid of thefollowing figures and detailed description below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 1.

FIG. 2 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate Form 1.

FIG. 3 is a thermal gravimetric analysis (TGA) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 1.

FIG. 4 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2.

FIG. 5 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate Form 2.

FIG. 6 is a thermal gravimetric analysis (TGA) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2.

FIG. 7 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 4.

FIG. 8 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 6.

FIG. 9 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 6.

FIG. 10 is a thermal gravimetric analysis (TGA) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 6.

FIG. 11 is a gravimetric vapor sorption (GVS) profile of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate Form 6.

FIG. 12 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 11.

FIG. 13 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate Form 11.

FIG. 14 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 12.

FIG. 15 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate Form 12.

FIG. 16 is a thermal gravimetric analysis (TGA) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 12.

FIG. 17 is a powder X-ray diffractogram (XRPD) of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 24.

FIG. 18 is a differential scanning calorimetry (DSC) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 24.

FIG. 19 is a thermal gravimetric analysis (TGA) profile for sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 24.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Abbreviations

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings.

“Sodium Salt” is meant to describe the sodium salt of4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid, and has the structure of formula (I).

“Form 1” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 1” are used interchangeably, and describe Form 1 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 3, Method B, in the Examples section below,and as described below, and represented by data shown in FIGS. 1, 2, and3.

“Form 2” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2” are used interchangeably, and describe Form 2 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 3, Method A, in the Examples section below,and as described below, and represented by data shown in FIGS. 4, 5, and6.

“Form 4” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 4” are used interchangeably, and describe Form 4 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 4, in the Examples section below, and asdescribed below, and represented by data shown in FIG. 7.

“Form 6” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 6” are used interchangeably, and describe Form 6 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 5, in the Examples section below, and asdescribed below, and represented by data shown in FIGS. 8, 9, 10, and11.

“Form 11” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 11” are used interchangeably, and describe describe Form 11 ofsodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 6, in the Examples section below, and asdescribed below, and represented by data shown in FIGS. 12 and 13.

“Form 12” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 12” are used interchangeably, and describe Form 12 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 7, in the Examples section below, and asdescribed below, and represented by data shown in FIGS. 14, 15, and 16.

“Form 24” or “sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 24” are used interchangeably, and describe Form 24 of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate,as synthesized in Example 8, in the Examples section below, and asdescribed below, and represented by data shown in FIGS. 17, 18, and 19.

As used herein, “crystalline” refers to a solid having a highly regularchemical structure. In particular, a crystalline Sodium Salt may beproduced as one or more single crystalline forms of the Sodium Salt. Forthe purposes of this application, the terms “crystalline form”, “singlecrystalline form” and “polymorph” are synonymous; the terms distinguishbetween crystals that have different properties (e.g., different XRPDpatterns, different DSC scan results). The term “polymorph” includespseudopolymorphs, which are typically different solvates of a material,and thus their properties differ from one another. Thus, each distinctpolymorph and pseudopolymorph of the Sodium Salt is considered to be adistinct single crystalline form herein.

“Substantially crystalline” refers to Salts that may be at least aparticular weight percent crystalline. Particular weight percentages are10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or anypercentage between 10% and 100%. In some embodiments, substantiallycrystalline refers to Salts that are at least 70% crystalline. In otherembodiments, substantially crystalline refers to Salts that are at least90% crystalline.

The term “solvate or solvated” means a physical association of acompound of this invention with one or more solvent molecules. Thisphysical association includes hydrogen bonding. In certain instances thesolvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate or solvated” encompasses both solution-phaseand isolable solvates. Representative solvates include, for example, ahydrate, ethanolates or a methanolate.

The term “hydrate” is a solvate wherein the solvent molecule is H₂O thatis present in a defined stoichiometric amount, and may for example,include hemihydrate, monohydrate, dihydrate, or trihydrate.

The term “mixture” is used to refer to the combined elements of themixture regardless of the phase-state of the combination (e.g., liquidor liquid/ crystalline).

The term “seeding” is used to refer to the addition of a crystallinematerial to initiate recrystallization or crystallization.

The term “antisolvent” is used to refer to a solvent in which compoundsof the invention are poorly soluble.

A “subject” is preferably a bird or mammal, such as a human, but canalso be an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), farm animals (e.g., cows,sheep, fowl, pigs, horses, and the like) and laboratory animals (e.g.,rats, mice, guinea pigs, and the like).

“Treating” or “treatment” means prevention, partial alleviation, or cureof a disease, disorder or condition. The compounds and compositions ofthis invention are useful in treating mitotic kinase mediated diseases,disorders or conditions, particularly Aurora kinase mediated diseases,disorders or conditions. Inhibiting mitotic kinase activity may serve totreat a number of diseases, involving cell survival, proliferation, andmigration, including cancer, as well as other cell-proliferativediseases.

As used herein, the term “Aurora kinase-mediated disorder” includes anydisorder, disease or condition which is caused or characterized by anincrease in Aurora kinase expression or activity, or which requiresAurora kinase activity. The term “Aurora kinase-mediated disorder” alsoincludes any disorder, disease or condition in which inhibition ofAurora kinase activity is beneficial. Aurora kinase-mediated disordersinclude proliferative disorders. Non-limiting examples of proliferativedisorders include chronic inflammatory proliferative disorders, e.g.,psoriasis and rheumatoid arthritis; proliferative ocular disorders,e.g., diabetic retinopathy; benign proliferative disorders, e.g.,hemangiomas; and cancer.

As used herein, the term “Aurora kinase” refers to any one of a familyof related serine/threonine kinases involved in mitotic progression. Avariety of cellular proteins that play a role in cell division aresubstrates for phosphorylation by Aurora kinase enzymes, including,without limitation, histone H3, p 53, CENP-A, myosin II regulatory lightchain, protein phosphatase-1, TPX-2, INCENP, survivin, topoisomerase IIalpha, vimentin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5 (in Xenopus),Ndc10p (in budding yeast), and D-TACC (in Drosophila). Aurora kinaseenzymes also are themselves substrates for autophosphorylation, e.g., atThr288. Unless otherwise indicated by context, the term “Aurora kinase”is meant to refer to any Aurora kinase protein from any species,including, without limitation, Aurora A, Aurora B, and Aurora C,preferably Aurora A or B. Preferably, the Aurora kinase is a humanAurora kinase.

“Pharmaceutically effective amount” is meant to describe an amount of acompound, composition, medicament or other active ingredient effectivein producing the desired therapeutic effect.

In one aspect, the present invention is directed to crystalline forms ofsodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateof formula (I). Accordingly, the present invention provides solvates ofsodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate of formula (I).

Provided herein is an assortment of characterizing information todescribe the crystalline forms of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(I). It should be understood, however, that not all such information isrequired for one skilled in the art to determine that such particularform is present in a given composition, but that the determination of aparticular form can be achieved using any portion of the characterizinginformation that one skilled in the art would recognize as sufficientfor establishing the presence of a particular form, e.g., even a singledistinguishing peak can be sufficient for one skilled in the art toappreciate that such particular form is present.

The Sodium Salt has properties that make it suitable for large scalepharmaceutical formulation manufacture. The crystalline forms of theSodium Salt described herein exhibit increased aqueous solubility overthe free acid compound of formula (II), which results in improvedabsorption of the active pharmaceutical ingredient. For example, inwater the free acid has a solubility of about 10 μg/mL. In water, Form 2has a solubility of about 8 mg/mL; Form 6 has a solubility of greaterthan about 10 mg/mL; and Form 24 has a solubility of about 8 mg/mL.

Embodiments of the invention are directed to the Sodium Salt, wherein atleast a particular percentage by weight of the Sodium Salt iscrystalline. In some embodiments, the Sodium Salt is substantiallycrystalline. Non-limiting examples of a crystalline Sodium Salt includea single crystalline form of the Sodium Salt or a mixture of differentsingle crystalline forms. An embodiment of the invention is alsodirected to a Sodium Salt, wherein at least a particular percentage byweight of the Sodium Salt is crystalline, that excludes one or moredesignated single crystalline forms from a particular weight percentageof Sodium Salt. Particular weight percentages may be 10%, 20%, 30%, 40%,50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and100%. When a particular percentage by weight of the Sodium Salt iscrystalline, the remainder of the Sodium Salt is the amorphous form ofthe Sodium Salt.

Alternatively, embodiments of the invention are directed to acrystalline Sodium Salt, wherein at least a particular percentage byweight of the crystalline Sodium Salt is a specific single crystallineform, a combination of particular crystalline forms, or excludes one ormore particular crystalline forms. Particular weight percentages may be10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or anypercentage between 10% and 100%.

Other embodiments of the invention are directed to the Sodium Salt beinga single crystalline form, or being substantially a designated singlecrystalline form. The single crystalline form may be a particularpercentage by weight of the Sodium Salt. Particular weight percentagesare 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or anypercentage between 10% and 100%. When a particular percentage by weightof a Sodium Salt is a single crystalline form, the remainder of theSodium Salt is some combination of amorphous form of the Sodium Salt,and one or more crystalline forms of the Sodium Salt excluding thesingle crystalline form. In some embodiments, the Sodium Salt is atleast 90% by weight of a single crystalline form. In some otherembodiments, the Sodium Salt is at least 95% by weight of a singlecrystalline form.

In the following description of the Sodium Salt, embodiments of theinvention may be described with reference to a particular crystallineform of the Sodium Salt, as characterized by one or more properties asdiscussed herein. The descriptions characterizing the crystalline formsmay also be used to describe the mixture of different crystalline formsthat may be present in a crystalline Sodium Salt. However, theparticular crystalline forms of the Sodium Salt may also becharacterized by one or more of the characteristics of the crystallineform as described herein, with or without regard to referencing aparticular crystalline form.

The processes and compounds of the present invention are furtherillustrated by the detailed descriptions and illustrative examples givenbelow.

Form 1

In one embodiment of the invention, a single crystalline form, Form 1,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 1, and data shown in Table 1, obtainedusing CuKa radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 1, as shown in Table 1.

TABLE 1 Angle Intensity 2-Theta ° % 4.44 13.7 8.77 63.1 9.40 18.6 10.23100 10.91 43.2 11.71 20.5 12.23 26.7 13.32 26.4 14.14 40.8 14.94 81.115.46 35.6 17.98 56.7 18.94 48.6 20.30 42.9 21.35 65.0 22.64 89.7 23.9774.3 24.71 62.0 25.67 73.5 26.53 68.8 28.89 61.8

In another embodiment of the invention, the peaks are identified at 2θangles of 8.77°, 10.23°, 14.94°, 21.35°, 22.64°, 23.97°, and 25.67°. Ina further particular embodiment, the peaks are identified at 2θ anglesof 10.23°, 14.94°, 22.64°, 23.97° , and 25.67°. In a further particular,embodiment, the peaks are identified at 2θ angles of 10.23°, 14.94°, and22.64°.

In another embodiment of the invention, Form 1 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 2. TheDSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by exothermic and endothermic transitions. The first isa strong endothermic transition with an onset temperature of about 61°C. with a melt at about 85° C., which is followed by a weak exothermictransition with an onset temperature of about 165 ° C. The third andfourth endothermic transitions are both weak with onset temperatures ofabout 202° C. and about 243° C., respectively. These temperatures havean error of ±2° C.

In another embodiment of the invention, Form 1 can be characterized bythermal gravimetric analysis (TGA) shown in FIG. 3. The TGA profilegraphs the percent loss of weight of the sample as a function oftemperature, the temperature rate change being about 10° C./min. Theweight loss represents a loss of about 7.4% of the weight of the sampleas the temperature is changed from 25° C. to 250° C.

In another embodiment of the invention, Form 1 is characterized by atleast one of the following features (I-i)-(I-iv):

-   -   (I-i) at least one of the X-ray powder diffraction peaks shown        in Table 1;    -   (I-ii) an X-ray powder diffraction pattern substantially similar        to FIG. 1;    -   (I-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 2; and    -   (I-iv) a thermal gravimetric analysis (TGA) profile        substantially similar to FIG. 3.

In a further embodiment of the invention, a single crystalline form ofForm 1 is characterized by two of the features (I-i)-(I-iv). In afurther embodiment of the invention, a single crystalline form of Form 1is characterized by three of the features (I-i)-(I-iv). In a furtherembodiment of the invention, a single crystalline form of Form 1 ischaracterized by all of the features (I-i)-(I-iv).

Form 2

In one embodiment of the invention, a single crystalline form, Form 2,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 4, and data shown in Table 2, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 4, as shown in Table 2.

TABLE 2 Angle Intensity 2-Theta ° % 3.44 100 4.76 9.1 6.80 10.7 7.80 7.79.36 16.5 10.29 16.3 11.58 30.3 11.96 8.3 12.24 8.8 13.11 52.1 13.7384.3 14.36 41.3 15.59 18.7 15.92 18.5 17.31 41.3 18.77 24.8 19.72 25.621.71 12.7 22.48 23.1 22.84 53.2 23.51 20.1 23.91 19.8 24.92 37.7 25.6519.0 25.91 27.0 26.39 33.6 27.00 19.6 28.57 18.7

In another embodiment of the invention, the peaks are identified at 2θangles of 3.44°, 13.11°, 13.73°, 14.36°, 17.31°, and 22.84°. In afurther particular embodiment, the peaks are identified at 2θ angles of3.44°, 13.11°, 13.73°, and 22.84°.

In another embodiment of the invention, Form 2 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 5. TheDSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by exothermic and endothermic transitions. The firstand second endothermic transitions have an onset temperature of about171° C. and about 226° C., respectively. The third transition is astrong endothermic transition with an onset temperature of about 258° C.with a melt at about 264° C. This transition is followed by twoexothermic transitions at about 289° C. and at about 309° C. Thesetemperatures have an error of ±2° C.

In another embodiment of the invention, Form 2 can be characterized bythermal gravimetric analysis (TGA) shown in FIG. 6. The TGA profilegraphs the percent loss of weight of the sample as a function oftemperature, the temperature rate change being about 10° C./min. Theweight loss represents a loss of about 22.8% of the weight of the sampleas the temperature is changed from 25° C. to 350° C.

In another embodiment of the invention, Form 2 is characterized by atleast one of the following features (II-i)-(II-iv):

-   -   (II-i) at least one of the X-ray powder diffraction peaks shown        in Table 2;    -   (II-ii) an X-ray powder diffraction pattern substantially        similar to FIG. 4;    -   (II-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 5; and    -   (II-iv) a thermal gravimetric analysis (TGA) profile        substantially similar to FIG. 6.

In a further embodiment of the invention, a single crystalline form ofForm 2 is characterized by two of the features (II-i)-(II-iv). In afurther embodiment of the invention, a single crystalline form of Form 2is characterized by three of the features (II-i)-(II-iv). In a furtherembodiment of the invention, a single crystalline form of Form 2 ischaracterized by all of the features (II-i)-(II-iv).

Form 4

In one embodiment of the invention, a single crystalline form, Form 4,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 7, and data shown in Table 3, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 7.

TABLE 3 Angle Intensity 2-Theta ° % 3.42 17.7 7.95 34.9 13.27 48.2 22.96100 25.89 98.8

In another embodiment of the invention, the peaks are identified at 2θangles of 13.27°, 22.96°, and 25.89°. In a further particularembodiment, the peaks are identified at 2θ angles of 22.96° and 25.89°.

In another embodiment of the invention, Form 4 is characterized by atleast one of the following features (III-i)-(III-ii):

-   -   (III-i) at least one of the X-ray powder diffraction peaks shown        in Table 3; and    -   (III-ii) an X-ray powder diffraction pattern substantially        similar to FIG. 7.

In a further embodiment of the invention, a single crystalline form ofForm 4 is characterized by both of the features (III-i)-(III-ii).

Form 6

In one embodiment of the invention, a single crystalline form, Form 6,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 8, and data shown in Table 4, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 8.

TABLE 4 Angle Intensity 2-Theta ° % 5.81 23.8 9.42 5.6 11.62 38.0 14.787.8 16.01 47.6 17.47 51.9 17.80 24.4 19.38 15.2 21.23 63.8 22.21 21.823.43 100 24.47 20.8 26.23 15.8 27.57 28.1 29.38 29.6

In another embodiment of the invention, the peaks are identified at 20angles of 11.62°, 16.01°, 17.47°, 21.23°, 23.43°, and 29.38°. In afurther particular embodiment, the peaks are identified at 2θ angles of16.01°, 17.47°, 21.23°, and 23.43°.

In another embodiment of the invention, Form 6 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 9. TheDSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by endothermic transitions. The first endothermictransition has an onset temperature of about 52° C. This is followed byan endothermic transition with an onset temperature of about 100° C. Thenext endothermic transition has an onset temperature of about 163° C.with a melt at about 181° C. The final endothermic transition has anonset temperature of about 196° C. These temperatures have an error of±2° C.

In another embodiment of the invention, Form 6 can be characterized bythe thermal gravimetric analysis (TGA) shown in FIG. 10, which graphsthe percent loss of weight of the sample as a function of temperature,the temperature rate change being about 10° C./min. The weight lossrepresents a loss of about 6.6% of the weight of the sample as thetemperature is changed from 25° C. to about 200° C.

In another embodiment of the invention, Form 6, can be characterized bythe vapor sorption profiles (GVS), as shown in FIG. 11. The profileshows the change in weight of the sample as the relative humidity (RH)of,the environment is changed by 10% RH intervals over a 0-90% RH rangeat a temperature of 25° C. Form 6 showed a 6% uptake between 0-90% RH.

In another embodiment of the invention, Form 6 is characterized by atleast one of the following features (IV-i)-(IV-v):

-   -   (IV-i) at least one of the X-ray powder diffraction peaks shown        in Table 4;    -   (IV-ii) an X-ray powder diffraction pattern substantially        similar to FIG. 8;    -   (IV-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 9;    -   (IV-iv) a thermal gravimetric analysis (TGA) substantially        similar to FIG. 10; and    -   (IV-v) a gravimetric vapor sorption (GVS) profile substantially        similar to FIG. 11.

In a further embodiment of the invention, a single crystalline form ofForm 6 is characterized by two of the features (IV-i)-(IV-v). In afurther embodiment of the invention, a single crystalline form of Form 6is characterized by three of the features (IV-i)-(IV-v). In a furtherembodiment of the invention, a single crystalline form of Form 6 ischaracterized by four of the features (IV-i)-(IV-v). In a furtherembodiment of the invention, a single crystalline form of Form 6 ischaracterized by all of the features (IV-i)-(IV-v).

Form 11

In one embodiment of the invention, a single crystalline form, Form 11,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 12, and data shown in Table 5, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 12.

TABLE 5 Angle Intensity 2-Theta ° % 3.37 6.5 9.73 5.7 10.60 9.7 10.9616.6 11.91 7.1 13.03 100 13.44 10.6 15.72 19.1 16.32 12.7 19.62 15.825.66 19.7 26.21 24.0 27.08 25.4

In another embodiment of the invention, the peaks are identified at 2θangles of 13.03°, 15.72°, 25.66°, 26.21°, and 27.08°. In a furtherparticular embodiment, the peaks are identified at 2θ angles of 13.03°,26.21°, and 27.08°.

In another embodiment of the invention, Form 11 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 13.The DSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by endothermic transitions. The first is an endothermictransition with an onset temperature of about 26° C. The secondendothermic transition has an onset temperature of about 58° C. Thethird endothermic transition has an onset temperature of about 255° C.,with a melt at about 272° C. These temperatures have an error of ±2° C.

In another embodiment of the invention, Form 11 is characterized by atleast one of the following features (V-i)-(V-iii):

-   -   (V-i) at least one of the X-ray powder diffraction peaks shown        in Table 5;    -   (V-ii) an X-ray powder diffraction pattern substantially similar        to FIG. 12; and    -   (V-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 13.

In a further embodiment of the invention, a single crystalline form ofForm 11 is characterized by two of the features (V-i)-(V-iii). Inanother further embodiment of the invention, a single crystalline formof Form 11 is characterized by all of the features (V-i)-(V-iii).

Form 12

In one embodiment of the invention, a single crystalline form, Form 12,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 14, and data shown in Table 6, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 14.

TABLE 6 Angle Intensity 2-Theta ° % 3.63 9.5 5.67 30.4 6.83 29.2 11.4232.7 12.72 78.5 13.46 35.8 14.11 29.9 14.40 30.8 15.39 27.0 21.26 66.021.89 52.6 25.57 100 29.50 35.8

In another embodiment of the invention, the peaks are identified at 2θangles of 12.72°, 13.46°, 21.26°, 21.89°, 25.57°, and 29.50°. In afurther particular embodiment, the identified at 2θ angles of 12.72°,21.26°, 21.89°, and 25.57°.

In another embodiment of the invention, Form 12 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 15.The DSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by two endothermic transitions. The first is has anonset temperature of about 38.8° C., with a melt at about 71.3° C. (peakmaximum). The second endothermic transition is a weak transition with anonset temperature of about 201.3° C. These temperatures have an error of±2° C.

In another embodiment of the invention, Form 12 can be characterized bythe thermal gravimetric analysis (TGA) shown in FIG. 16, which graphsthe percent loss of weight of the sample as a function of temperature,the temperature rate change being about 10° C./min. The weight lossrepresents a loss of about 18.3% of the weight of the sample as thetemperature is changed from 25° C. to 250° C.

In another embodiment of the invention, Form 12 is characterized by atleast one of the following features (VI-i)-(VI-iv):

-   -   (VI-i) at least one of the X-ray powder diffraction peaks shown        in Table 6;    -   (VI-ii) an X-ray powder diffraction pattern substantially        similar to FIG. 14;    -   (VI-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 15; and    -   (VI-iv) a thermal gravimetric analysis (TGA) substantially        similar to FIG. 16.

In a further embodiment of the invention, a single crystalline form ofForm 12 is characterized by two of the features (VI-i)-(VI-iv). In afurther embodiment of the invention, a single crystalline form of Form12 is characterized by three of the features (VI-i)-(VI-iv). In afurther embodiment of the invention, a single crystalline form of Form12 is characterized by all of the features (IV-i)-(IV-iii).

Form 24

In one embodiment of the invention, a single crystalline form, Form 24,of the Sodium Salt is characterized by the X-ray powder diffraction(XRPD) pattern shown in FIG. 17, and data shown in Table 7, obtainedusing CuKα radiation. In a particular embodiment of the invention, thepolymorph can be characterized by one or more of the peaks taken fromFIG. 17.

TABLE 7 Angle Intensity 2-Theta ° % 7.96 6.4 8.86 7.3 10.49 36.2 10.93100 11.81 26.5 12.90 10.7 13.46 16.1 13.85 22.7 14.82 17.1 15.67 91.316.17 39.8 16.39 40.2 17.22 16.3 18.01 24.0 19.76 44.2 20.16 34.4 22.0550.6 22.90 81.1 23.38 52.7 23.84 56.2 25.05 33.2 25.70 46.0 26.18 39.726.91 87.4

In another embodiment of the invention, the peaks are identified at 2θangles of 10.93°, 15.67°, 19.76°, 22.05°, 22.90°, 23.38°, 23.84°, and26.91°. In a further particular embodiment, the peaks are identified at2θ angles of 10.93°, 15.67°, 22.90°, 23.84°, and 26.91°.

In another embodiment of the invention, Form 24 can be characterized bythe differential scanning calorimetry profile (DSC) shown in FIG. 18.The DSC graph plots the heat flow as a function of temperature from asample, the temperature rate change being about 10° C./min. The profileis characterized by several exothermic and endothermic transitions. Thefirst is an endothermic transition with an onset temperature of about62.4° C., with a melt at about 87.5° C. (peak maximum), followed by aweak endothermic transition with an onset temperature of about 105.3° C.The next is an exothermic transition at about 175.8° C., followed by anendothermic transition has an onset temperature of about 221.0° C., witha melt at about 231.9° C. (peak maximum). The final transition isendothermic and has an onset temperature of about 254.2° C., with a meltat about 259.3° C. (peak maximum). These temperatures have an error of±2° C.

In another embodiment of the invention, Form 24 can be characterized bythe thermal gravimetric analysis (TGA) shown in FIG. 19. The TGA profilegraphs the percent loss of weight of the sample as a function oftemperature, the temperature rate change being about 10° C./min. Theweight loss represents a loss of about 7.1% of the weight of the sampleas the temperature is changed from 25° C. to 250° C.

In another embodiment of the invention, Form 24 is characterized by atleast one of the following features (VII-i)-(VII-iv):

-   -   (VII-i) at least one of the X-ray powder diffraction peaks shown        in Table 7;    -   (VII-ii) an X-ray powder diffraction pattern substantially        similar to FIG. 17;    -   (VII-iii) a differential scanning calorimetry (DSC) profile        substantially similar to FIG. 18; and    -   (VII-iv) a thermal gravimetric analysis (TGA) profile        substantially similar to FIG. 19.

In a further embodiment of the invention, a single crystalline form ofForm 24 is characterized by two of the features (VII-i)-(VII-iv). In afurther embodiment of the invention, a single crystalline form of Form24 is characterized by three of the features (VII-i)-(VII-iv). In afurther embodiment of the invention, a single crystalline form of Form24 is characterized by all of the features (IV-i)-(IV-iv).

Other embodiments of the invention are directed to a single crystallineform of the Sodium Salt characterized by a combination of theaforementioned characteristics of any of the single crystalline formsdiscussed herein. The characterization may be by any combination of oneor more of the XRPD, TGA, DSC, and water sorption/desorptionmeasurements described for a particular polymorph. For example, thesingle crystalline form of the Sodium Salt may be characterized by anycombination of the XRPD results regarding the position of the majorpeaks in a XRPD scan; and/or any combination of one or more of the cellparameters derived from data obtained from a XRPD scan. The singlecrystalline form of the Sodium Salt may also be characterized by TGAdeterminations of the weight loss associated with a sample over adesignated temperature range; and/or the temperature at which aparticular weight loss transition begins. DSC determinations of thetemperature associated with the maximum heat flow during a heat flowtransition and/or the temperature at which a sample begins to undergo aheat flow transition may also characterize the crystalline form. Weightchange in a sample and/or change in sorption/desorption of water permolecule of anhydrous Sodium Salt as determined by watersorption/desorption measurements over a range of relative humidity(e.g., 0% to 90%) may also characterize a single crystalline form of theSodium Salt.

Examples of combinations of single crystalline form characterizationsusing multiple analytical techniques include the location of at leastone of the major peaks of a XRPD scan and the temperature associatedwith the maximum heat flow during one or more heat flow transitionsobserved by a corresponding DSC measurement; the location of at leastone of the major peaks of a XRPD scan and one or more weight lossesassociated with a sample over a designated temperature range in acorresponding TGA measurement; the location of at least one of the majorpeaks of a XRPD scan, the temperature associated with the maximum heatflow during one or more heat flow transitions observed by acorresponding DSC measurement, and one or more weight losses associatedwith a sample over a designated temperature range in a corresponding TGAmeasurement; and the location of at least one of the major peaks of aXRPD scan, the temperature associated with the maximum heat flow duringone or more heat flow transitions observed by a corresponding DSCmeasurement, one or more weight losses associated with a sample over adesignated temperature range in a corresponding TGA measurement, and thechange in sorption/desorption of water per molecule of anhydrous salt asdetermined by water sorption/desorption measurements over a range ofrelative humidity. As well, each of the aforementioned examples mayreplace the use of the location of at least one of the major peaks of aXRPD scan with one or more cell parameters of the single crystallineform.

The combinations of characterizations that are discussed above may beused to describe any of the polymorphs of the Sodium Salt discussedherein (e.g., Form 1, 2, 4, 6, 11, 12, or 24).

In some embodiments, Form 6 can be converted to give Form 2. In someother embodiments, Form 6 can be converted to give Form 2 by heating ata temperature of between about 25° C. and about 50° C. In yet some otherembodiments, Form 6 can be converted to give a mixture of Form 6 andForm 2.

In some embodiments, Form 11 can be converted to give Form 1, Form 2, ora mixture therof. In some other embodiments, Form 11 can be converted togive Form 1, Form 2, or a mixture thereof by heating at a temperature ofbetween about 25° C. and about 50° C. In yet some other embodiments,Form 11 can be converted to give a mixture of any combination of Form 1,Form 2, Form 11, and Form 24.

In some embodiments, Form 1 can be converted to give Form 24. In someother embodiments, Form 1 can be converted to give Form 24 by standingat ambient conditions. In yet some other embodiments, Form 1 can beconverted to give a mixture of any combination of Form 1, Form 2, andForm 24.

In some embodiments, Form 4 can be converted to give Form 24. In someother embodiments, Form 4 can be desolvated to give Form 24 by dryingunder ambient conditions. In yet some other embodiments, Form 4 can beconverted to give a mixture of any combination of Form 1, Form 2, Form 4and Form 24.

In some embodiments, Form 24 can be converted to give Form 1, Form 2, ora mixture thereof. In some other embodiments, Form 24 can be convertedto give Form 1 by heating at a temperature of between about 50° C. andabout 75° C. In some other embodiments, Form 24 can be converted to giveForm 2 by heating at a temperature of between about 25° C. and about 50°C. In yet some other embodiments, Form 24 can be converted to give amixture of any combination of Form 1, Form 2, and Form 24.

Pharmaceutical Compositions and Methods

The pharmacological properties of the Sodium Salt, or crystalline formsthereof, is such that it is suitable for use in the treatment ofpatients suffering from or subject to diseases, disorders or conditionsmediated by Aurora kinase, including, but not limited to, proliferativedisorders such as chronic inflammatory proliferative disorders, e.g.,psoriasis and rheumatoid arthritis; proliferative ocular disorders,e.g., diabetic retinopathy; benign proliferative disorders, e.g.,hemangiomas; and cancer.

In certain embodiments of the invention, a method for treating cancer isprovided comprising administering a pharmaceutically effective amount ofthe Sodium Salt, or a crystalline form thereof, or a pharmaceuticalcomposition thereof, to a subject in need thereof.

In some embodiments, the cancer is a solid tumor. Non-limiting examplesof solid tumors that can be treated by the methods of the inventioninclude pancreatic cancer; bladder cancer; colorectal cancer; breastcancer, including metastatic breast cancer; prostate cancer, includingandrogen-dependent and androgen-independent prostate cancer; renalcancer, including, e.g., metastatic renal cell carcinoma; hepatocellularcancer; lung cancer, including, e.g., non-small cell lung cancer(NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of thelung; ovarian cancer, including, e.g., progressive epithelial or primaryperitoneal cancer; cervical cancer; gastric cancer; esophageal cancer;head and neck cancer, including, e.g., squamous cell carcinoma of thehead and neck; melanoma; neuroendocrine cancer, including metastaticneuroendocrine tumors e.g., neuroblastoma; brain tumors, including,e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma; bone cancer; and softtissue sarcoma.

In some other embodiments, the cancer is a hematologic malignancy.Non-limiting examples of hematologic malignancy include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In still other embodiments, the cancer is selected from the groupconsisting of NHL, AML, MDS, colorectal cancer, ovarian cancer, breastcancer, gastric cancer, prostate cancer, and pancreatic cancer.

Some embodiments of the invention are directed toward a solidpharmaceutical composition comprising at least one pharmaceuticallyacceptable carrier or diluent; and the Sodium Salt, or a crystallineform thereof. In other embodiments, the solid pharmaceutical compositioncomprises at least one pharmaceutically acceptable carrier or diluent,and a substantially crystalline Sodium Salt. In other embodiments, thesolid pharmaceutical composition comprises at least one pharmaceuticallyacceptable carrier or diluent, and the Sodium Salt, wherein the SodiumSalt is at least 95% by weight a single crystalline form; the singlecrystalline forms being described herein. In other embodiments, thesolid pharmaceutical composition comprises at least one pharmaceuticallyacceptable carrier or diluent, and the Sodium Salt, wherein the SodiumSalt is substantially a single crystalline form; the single crystallineforms being described herein. In other embodiments, these solidcompositions optionally further comprise one or more additionaltherapeutic agents.

Some embodiments of the invention are directed toward a liquidpharmaceutical composition comprising at least one pharmaceuticallyacceptable carrier or diluent; and the compound4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid of formula (II). In some embodiments, the liquid pharmaceuticalcomposition is prepared using a substantially crystalline Sodium Salt.In other embodiments, the liquid pharmaceutical composition is preparedusing the Sodium Salt, wherein the Sodium Salt is at least 95% by weighta single crystalline form; the single crystalline forms being describedherein. In other embodiments, the liquid pharmaceutical is preparedusing the Sodium Salt, wherein the Sodium Salt is substantially a singlecrystalline form; the single crystalline forms being described herein.In other embodiments, these liquid compositions optionally furthercomprise one or more additional therapeutic agents.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise at least one pharmaceuticallyacceptable carrier, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, gelatin or polymeric capsule shell, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, sodium bicarbonate,or potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blockpolymers, wool fat, sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil; safflower oil; sesame oil; olive oil; corn oil andsoybean oil; glycols; such a propylene glycol or polyethylene glycol;esters such as ethyl oleate and ethyl laurate; agar; buffering agentssuch as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

The Sodium Salt, or a single crystalline form thereof, or apharmaceutical composition thereof, according to the method of thepresent invention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The Sodium Salt, or a single crystalline form thereof, or apharmaceutical composition thereof, are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disease beingtreated and the severity of the disease; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

The Sodium Salt, or a single crystalline form thereof, or apharmaceutical composition thereof, can be administered to humans andother animals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), bucally, as an oral or nasal spray, or the like, depending onthe severity of the infection being treated. In certain embodiments, thecompounds of the invention may be administered orally or parenterally atdosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably fromabout 1 mg/kg to about 25 mg/kg, of subject body weight per day, one ormore times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.Alternatively, compositions for rectal or vaginal administration aregels or creams that can be prepared by mixing compounds with suitablenon-irritating excipients such as oils or water to solubilize thecompound and polymers and fatty alcohols can be added to thicken theformulation to increase the residual time in the rectal or vaginalcavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound may optionally be mixed with at least one inert,pharmaceutically acceptable excipient or carrier such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol, microcrystalline cellulose, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, croscarmellose sodium, potato or tapioca starch,alginic acid, certain silicates, crospovidone, and sodium carbonate, e)solution retarding agents such as paraffin, f) absorption acceleratorssuch as quaternary ammonium compounds, g) wetting agents such as, forexample, cetyl alcohol and glycerol monostearate, h) absorbents such askaolin and bentonite clay, and i) lubricants such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, sodium stearyl fumarate, and mixtures thereof. In the case ofcapsules, tablets and pills, the dosage form may also comprise bufferingagents or a flow aid such as colloidal silicon dioxide. In otherembodiments, the active compound may be encapsulated in a gelatin orpolymeric capsule shell without any additional agents (neat capsuleshell).

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. The solid dosage forms may optionally contain opacifying agents andcan also be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules using such excipients as lactose or milksugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

In some embodiments, the solid dosage form comprises the Sodium Salt, ora crystalline form thereof, and at least one of sodium stearyl fumarate,crospovidone, mannitol and colloidal silicon dioxide.

In some embodiments, the solid dosage form comprises a tablet with afilm coating. In some other embodiments, the solid dosage form comprisesabout 10% of a lubricant. In some other embodiments, the solid dosageform comprises about 9% of a disintegrant. In some embodiments, thesolid dosage form has a high drug loading. In some embodiments, thesolid dosage form comprises about 30% to about 60% by weight of theSodium Salt, or a crystalline form thereof. In some embodiments, thesolid dosage form comprises about 40% to about 50% by weght of theSodium Salt, or a crystalline form thereof.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The Sodium Salt, or a single crystalline form thereof, or pharmaceuticalcomposition thereof, may be used in an application of monotherapy totreat a disorder, disease or symptom, it also may be used in combinationtherapy, in which the use of an inventive compound or composition(therapeutic agent) is combined with the use of one or more othertherapeutic agents for treating the same and/or other types ofdisorders, symptoms and diseases. Combination therapy includesadministration of the therapeutic agents concurrently or sequentially.Alternatively, the therapeutic agents can be combined into onecomposition which is administered to the patient.

Another aspect of the invention describes a process for the synthesis ofthe compound of Formula (II) as outlined herein.

EXAMPLES Abbreviations

Abbreviations ca approximately DMSO dimethylsulfoxide DSC differentialscanning calorimetry EtOH ethanol GC gas chromatography GVS gravimetricvapor sorption h hours HPLC high performance liquid chromatography KFKarl Fischer min minutes m/z mass to charge MS mass spectrum MTBEtent-butyl methyl ether NMR nuclear magnetic resonance RT roomtemperature TGA thermal gravimetric analysis XRPD X-ray powderdiffractionGeneral Methods

¹H NMR: Proton nuclear magnetic resonance spectra are obtained oneither:

-   -   i) a Brucker 400 MHz spectrometer equipped with an auto-sampler        (samples are prepared in d₆-DMSO, unless otherwise stated); or    -   ii) a Varian Mercury 300 MHz spectrometer.

Mass Spectrometry: Mass spectrometry studies are run on aThermo-Finnigan LCQ Deca-XP ion trap mass spectrometer. The electrosprayion source was used in both positive and negative modes with a highvoltage of 5 kv, sheath gas flow rate of 35 arb, capillary temperatureof 275° C., capillary voltage of 9 V and tube lens offset of 35 V. Ananalyte was dissolved in acetonitrile to generate a 0.5 mg/ml solution.An Agilent 1100 HPLC system was used for LC-Mass spectrometry flowanalysis. The pump flow rate was 1.0 ml/minute. 10 μl of each samplesolution was injected from the autosampler into a T-joint. About 2% ofthe solution from the T-joint was infused into the mass spectrometer.

X-Ray Powder Diffractometry (XRPD): X-ray powder diffraction patternsare acquired on either:

-   -   i) a Bruker AXS/Siemens D5000 diffractometer using Cu Kα        radiation (40 kV, 40 mA), θ-θ goniometer, automatic divergence        and receiving slits, a graphite secondary monochromator and a        scintillation counter. The instrument is performance checked        using a certified corundum standard (NIST 1976). Samples run        under ambient conditions are prepared as flat plate specimens        using powder as received without grinding. Approximately 35 mg        of the sample is gently packed into a cavity cut into polished,        zero-background (510) silicon wafer. The sample is rotated in        its own plane during analysis. Samples run under non-ambient        conditions are packed into a stainless steel cavity sample        holder equipped with a Pt 100 thermocouple. Low temperature data        are collected using an Anton Paar TTK450 variable temperature        camera attached to the Bruker AXS/Siemens D5000 diffractometer.        Instrumental conditions for the low temperature scan are similar        to those described for the flat plate samples above. All XRPD        analyses are performed using the Diffrac Plus XRD Commander        software v2.3.1. Diffraction data are reported using Cu Kα1        (λ=1.5406 Å), after the Kα2 component has been stripped using        EVA, the powder patterns are indexed by the ITO method using        WININDEX and the raw lattice constants refined using WIN-METRIC;        or    -   ii) a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation        (40 kV, 40 mA), automated XYZ stage, laser video microscope for        auto-sample positioning and a HiStar 2-dimensional area        detector. X-ray optics consists of a single Göbel multilayer        mirror coupled with a pinhole collimator of 0.3 mm. The beam        divergence, i.e. the effective size of the X-ray beam on the        sample, is approximately 5 mm. A θ-θ continuous scan mode is        employed with a sample, detector distance of 20 cm which gives        an effective 2θ range of 3.2°-29.7°. Typically, the sample would        be exposed to the X-ray beam for 120 seconds. Samples run under        ambient conditions are prepared as flat plate specimens using        powder without grinding. Approximately 1-2 mg of the sample is        lightly pressed on a glass slide to obtain a flat surface.        Samples run under non-ambient conditions are mounted on a        silicon wafer with heatconducting compound. The sample is then        heated to the appropriate temperature at ca. 20° C. per min and        subsequently held isothermally for ca 1 minute before data        collection is initiated; or    -   iii) a Brucker AZS D8-Advance X-ray Diffractometer. About 50 mg        of sample is gently flattened into a 50 mm diameter quartz        sampling pan for powder measurements. The sample is run as a        continuous scan from 2.9°2θ to 29.6°2θ using 2θ/θ locked coupled        angles. Each angle interval is 0.05°2θ and the data are        collected for 2 seconds. The sample run occurs under ambient        conditions and data analysis is performed using EVA version 9.0        software.

Differential Scanning calorimetry (DSC): Differential scanningcalorimetry (DSC) data are collected on either:

-   -   i) a TA Instruments Q1000 differential scanning calorimeter        equipped with a 50 position auto-sampler. The energy and        temperature calibration standard is indium. Samples are heated        at a rate of 10° C. per minute between 25° C. and 300° C. A        nitrogen purge flowing at 30 mL per minute is maintained over        the sample during a scan. Between 0.5 mg and 3 mg of sample is        analyzed. All samples are crimped in a hermetically sealed        aluminum pan with a pinhole to alleviate the pressure        accumulated from the solvent vapor; or    -   ii) a TA Instruments DSC Q2000 differential scanning        calorimeter. Between 1 mg and 2 mg of sample is sealed in an        aluminum pan with a lid. The sample is heated at a ramp rate of        10° C. per minute between 25° C. and 350° C., while the nitrogen        sample puge is kept constant at 50 mL/min. The thermograms are        analyzed using Thermal Advantage for Q Series software.

Thermal Gravimetric Analysis (TGA): Thermal gravimetric analysis (TGA)data are collected on a TA Instruments Q500 thermal gravimetricanalyzer, equipped with a 16 position auto-sampler. The instrument iscalibrated using certified Alumel. Typically 3 mg to 10 mg of sample isloaded onto a pre-tared platinum crucible and aluminum DSC pan, heatedat 10° C. per minute from ambient temperature to 350° C. A nitrogenpurge flowing at 60 mL per minute is maintained over the sample duringmeasurements. The thermograms are analyzed using Thermal Advantage for QSeries software.

Example 1 Synthesis of(5-chloro-2-iodophenyl)(2-fluoro-6-methoxyphenyl)methanone (3)

Step 1: (5-chloro-2-iodophenyl)(2,6-difluorophenyl)methanone (2)

Into a reactor at room temperature was added(2-amino-5-chlorophenyl)(2,6-difluorophenyl)methanone (1, 60.0 kg, 224mol) and acetic acid (427 L). The mixture was stirred until all solidsfully dissolved, filtered and washed with acetic acid (9.47 L).Concentrated HCl (156 L) was added over a minimum of 30 minutes at 20 to25° C. and the resulting mixture was cooled to 0 to 5° C. A solution ofsodium nitrite (18.6 kg, 269 mol) in water (88.0 L) was added whilemaintaining the reaction temperature between 0 and 5° C. The mixture wasstirred for 1 h at 0 to 5° C. Water (270 L) and isopropyl acetate (717L) were then added at 0 to 5° C. A solution of potassium iodide (50.2kg, 303 mol) in water (133 L) was added over 1 h at 0 to 5° C. Thereaction mixture was stirred for 30 min and warmed to 20 to 25° C. over1.5 h. The layers were separated and the organic phase was washed with adilute brine solution (22 kg NaCl in 200 L water) and a sodium carbonatesolution (175 kg Na₂CO₃ in 523 L water). The resulting organic layer waswashed twice with a sodium ascorbate solution (15.8 kg in 188 L waterfor each wash) followed by water (200 L). The organic phase wasconcentrated using a maximum 50° C. jacket temperature until 430 L ofsolvent was removed. Heptane (400 L) was added and the mixture wasconcentrated using a 50° C. jacket temperature until 395 L of solventwere removed. 2-Butanol (398 L) was added and the mixture wasconcentrated using a maximum 60° C. jacket temperature until 322 L ofsolvent were removed. An additional portion of 2-butanol (398 L) wasadded and the mixture was concentrated using a 70° C. jacket temperatureuntil 390 L of solvent were removed. The reaction mixture was cooled to−5 to −8° C., stirred for 2 h, filtered and washed with 2-butanol(2×84.2 L) at −5 to 0° C. The resulting wet cake was dried at 40 to 50°C. under vacuum to provide 67.6 kg (80% yield) of 2. ¹H NMR (300 MHz,CDCl₃) δ 7.89 (d, J=8.2 Hz, 1H), 7.51 (m, 1H), 7.44 (d, J=2.3 Hz, 1H),7.18 (dd, J=2.3, 8.2 Hz, 1H), 7.00 (m, 2H); Elemental Anal. Calcd. forC₁₃H₆ClF₂IO: C, 41.25; H, 1.60; Cl, 9.37; F, 10.04; I, 33.52; O, 4.23.Found: C, 41.36; H, 1.65; Cl, 9.51; F, 10.03; I, 33.41; O, 4.04.

Step 2: (5-chloro-2-iodophenyl)(2-fluoro-6-methoxyphenyl)methanone (3)

Into a reactor at room temperature was added 2 (67.6 kg, 179 mol) andMTBE (344 L). The mixture was warmed to 40° C. and stirred for 30 minuntil solids fully dissolved. The mixture was then cooled to 25 to 30°C. Sodium methoxide as a 25% w/w solution in methanol (45.2 kg, 209 mol)was added over a minimum of 90 min at 25 to 30° C. The reaction mixturewas stirred for at least 2 h until >99.0% conversion was obtained byHPLC analysis. Water (483 L) was added slowly over 30 min whilemaintaining the temperature between 20 and 25° C. The layers wereseparated and the aqueous phase was extracted with MTBE (77 L). Thecombined organic extracts were washed with a dilute brine solution (38kg NaCl in 342 L water). The organic layer was filtered, washed withwater (242 L) and the organic phase was filtered. The resulting organicphase was concentrated until 360 L of solvent were removed whilemaintaining the internal temperature below 70° C. Isobutanol (302 L) wasadded and the mixture was concentrated while maintaining the internaltemperature below 70° C. until 307 L of solvent were removed. A secondportion of isobutanol (330 L) was added and the mixture was concentratedwhile maintaining the internal temperature below 70° C. until 210 L ofsolvent were removed. The mixture was heated to 60 to 85° C. until aclear solution was obtained and cooled to 50° C. A slurry of seedcrystals (50 g in 150 mL isobutanol) was added and the mixture wascooled to 40° C. A second slurry of seed crystals (30 g in 60 mLisobutanol) was added and the mixture was cooled to 20 to 25° C. over aminimum of 3 h. The resulting mixture was stirred an additional 2 h. Themixture was filtered and washed with isobutanol (2×65 L). The resultingwet cake was dried at 20 to 35° C. under vacuum to provide 50.9 kg ofcrude 3. Into a separate reactor was charged crude 3 and isobutanol (69L). The mixture was heated to 75 to 80° C. until a clear solution wasobtained. The reaction mixture was cooled to 55° C. and a slurry of seedcrystals (50 g in 500 mL isobutanol) was added. The mixture was stirredfor 30 min at 55° C., cooled to 20 to 25° C. over a minimum of 3 h andstirred an additional 2 h. The mixture was filtered and washed withisobutanol (2×31 L). The wet cake was dried under vacuum at 40° C. toprovide 46.0 kg (66% yield) of purified 3. ¹H NMR (300 MHz, CDCl₃) δ7.88 (d, J=8.2 Hz, 1H), 7.42 (m, 2H), 7.13 (dd, J=2.3, 8.2 Hz), 6.76 (m,2H), 3.73 (s, 3H); MS (ESI) m/z 391.2 (M+H⁺, 30%).

Example 2 Synthesis of 4-{[amino(imino)methyl]amino}-2-methoxybenzoicacid hydrochloride (6)

Step 1: methyl 4-{[amino(imino)methyl]amino}-2-methoxybenzoate nitrate(5)

Into a reactor at room temperature was added methyl4-amino-2-methoxybenzoate (4, 38 kg, 210 mol) and methanol (224 L). Themixture was stirred at 25 to 30° C. for 30 min. Aqueous cyanamide (50%w/w, 43 kg, 512 mol) was added over a minimum of 30min at 20 to 25° C.The reaction mixture was heated to reflux using a maximum jackettemperature of 75° C. Concentrated nitric acid (45 kg, 499 mol) wasadded over a minimum of 60 min. The resulting mixture was heated atreflux for 2 h. A suspension of seed crystals (16 g in 600 mL methanol)was added and the mixture was stirred using a 75° C. jacket temperaturefor 60 to 90 min. The mixture was cooled to 20 to 25° C. over at least 2h and stirred for an additional 2 h. The mixture was filtered and washedwith methanol (180 L) while stirring for 1 h. The wet cake was washed asecond time with methanol (180 L) while stirring for 1 h. The resultingwet cake was dried under vacuum at 25° C. to provide 30.0 kg (50% yield)of 5. ¹H NMR (300 MHz, DMSO-d₆) δ 9.82 (s, 1H), 7.70 (d, J=8.2 Hz, 1H),7.57 (s, 4H), 6.97 (d, J=2.3 Hz, 1H), 6.84 (dd, J=2.3, 8.2 Hz, 1H), 3.81(s, 3H), 3.76 (s, 3H); MS (ESI) m/z 224.4 (M⁺, 100%).

Step 2: 4-{[amino(imino)methyl]amino}-2-methoxybenzoic acidhydrochloride (6)

Into a reactor was added 5 (29.8 kg, 104 mol) and water (475 L). Themixture was heated to 75 to 80° C. and concentrated HCl (107 kg, 1051mol) was added over a minimum of 30 min while maintaining thetemperature between 75 and 80° C. The reaction mixture was stirred for 3h at 75 to 80° C. The reaction mixture was sampled and the % conversionwas determined by HPLC analysis. The mixture was heated at 75 to 80° C.until the % conversion reached >97.3% or until at total reaction time of7 h. The reaction was cooled to 20 to 25° C. over a minimum of 3 h andstirred for an additional 2 h at 20 to 25° C. The reaction was filteredand washed with 16% w/w HCl (2×35 kg), water (82 L) and heptane (2×120L). The resulting wet cake was dried under vacuum at 35 to 50° C. toprovide 23.9 kg (93% yield) of 6. ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s,1H), 7.72 (s, 4H), 7.69 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.81(dd, J=2.3, 8.8 Hz, 1H), 3.80 (s, 3H); MS (ESI) m/z 210.4 (M⁺, 100%).

Example 3 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphentyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 1 and Form 2.

Step 1: tert-butyl prop-2-yn-1-ylcarbamate (7)

Into a reactor was added propagylamine (10.0 kg, 182 mol) and MTBE (154L). A Boc₂O solution was prepared by dissolving Boc₂O (41.3 kg, 190 mol)in MTBE (61 L) and transferred over a minimum of 60 min to thepropargyamine solution while maintaining a temperature between 23 and28° C. The reaction mixture was stirred for at least 1 h until ≧98.0%conversion was obtained by GC analysis. A solution of sodium bisulfate(5.6 kg of NaHSO₄ in 44 L water) was added over a minimum of 15 minwhile maintaining the temperature between 20 and 25° C. and stirred for20 min. The phases were separated and washed as before with a solutionof sodium bisulfate (5.6 kg of NaHSO4 in 44 L water). The resultingorganic phase was washed with a sodium bicarbonate solution (4.0 kg in44 L water) and water (2×47 L). The organic phase was concentrated usinga maximum jacket temperature of 40° C. until 62 kg remained in thereactor. Heptane (186 L) is added over a minimum of 20 min whilemaintaining the temperature between 35 and 40° C. The mixture wasconcentrated using a maximum jacket temperature of 40° C. until 70 kgremained in the reactor. The mixture was cooled to 0 to 5° C. over aminimum of 3 h and stirred for 1 h at 0 to 5° C. The mixture wasfiltered and washed with heptane at 0 to 5° C. (2×15 L). The wet cakewas dried under vacuum at 25 to 30° C. to provide 20.9 kg (74% yield of7. ¹H NMR (300 MHz, CDCl₃) δ 4.70 (s, 1H), 3.92 (d, J=Hz, 2H), 2.22 (m,1H), 1.45 (s, 9H); Elemental Anal. Calcd. for C₈H₁₃NO₂: C, 61.91; H,8.44; N, 9.03; O, 20.62. Found: C, 61.99; H, 8.36; N, 9.11; O, 20.54.

Step 2: tert-butyl{3-[4-chloro-2-(2-fluoro-6-methoxybenzoyl)phenyl]prop-2-yn-1-yl}carbamate(8)

Into a reactor was added 3 (15.0 kg, 38.4 mol), 7 (7.2 kg, 46.4 mol) andcyclohexane (230 L). The suspension was degassed three times for atleast 3 min each time using a vacuum-nitrogen cycle. Diethylamine (8.6kg, 119 mol) was added and the reaction mixture was heated to 28 to 33°C. Dichlorobis(triphenylphosphine)palladium (II) (0.134 kg, 0.192 mol)and copper (II) iodide (0.037 kg, 0.192 mol) were added and the mixturewas stirred at 28 to 33° C. for at least 15 h until ≧99.0% conversionwas obtained by HPLC analysis. Water (68 L) followed by MTBE (92 L) wereadded. The reaction mixture was heated to 45 to 50° C. and stirred for aminimum of 30 min and until all solids fully dissolved. The phases wereseparated at 45 to 50° C. and the organic phase was washed with water(2×68 L) at 45 to 50° C. The resulting organic phase was filtered andthe reactor was rinsed with MTBE (32 L) at 45 to 50° C. The rinse wasthen transferred to the second reactor containing the filtrate via thefilter membrane. The combined filtrate was concentrated under vacuumusing a jacket temperature of 45 to 50° C. until 225 kg remained in thereactor. The mixture was cooled to 35 to 40° C. and a slurry of seedcrystals (10 g of 8 in 500 mL cyclohexane) was added. The reactionmixture was stirred for 60 min at 35 to 40° C. and concentrated undervacuum using a jacket temperature of 45 to 50° C. until 144 kg remainedin the reactor. The mixture was cooled to 18 to 23° C. over a minimum of2 h and stirred for an additional 2 h at 18 to 23° C. The resultingsuspension was filtered and washed with cyclohexane (2×53 L). The wetcake was dried under vacuum at 40 to 45° C. to provide 16.0 kg (80%yield) of 8. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (s, 1H), 7.41 (m, 3H), 6.77(m, 2H), 4.43 (s, 1H), 3.88 (d, J=5.3 Hz, 2H), 3.74 (s, 3H), 1.46 (s,9H); MS (ESI) m/z 318.4 (M+H⁺-Boc, 23%), 362.4 (M+H⁺-t-butyl cation,20%).

Step 3:8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)-3,4-dihydro-5H-2-benzazepin-5-one(9)

Trifluoroacetic acid (158 L) and water (8.3 L) were added to a reactor.A solution of 8 (37.8 kg, 90.5 mol) in dichloromethane (63 L) was addedvia a second reactor to the trifluoroacetic acid solution over a minimumof 60 min while maintaining the temperature between 20 and 30° C. Thereactor containing the solution of 8 was rinsed with dichloromethane (19L) and transferred to the reaction mixture while maintaining thetemperature between 20 and 30° C. The mixture was heated to 30 to 35° C.and stirred for at least 19 h until ≧98.0% conversion was obtained byHPLC analysis. The mixture was concentrated under vacuum at 35 to 45° C.until 76 to 79 kg remained in the reactor. Dichloromethane (424 L) wasadded while maintaining the internal temperature between 20 and 30° C.N,N-Diisopropylethylamine (64 kg, 495 mol) was added over a minimum of30 min while maintaining the temperature between 20 and 30° C. If the pHwas <8.0 then 5 L portions of N,N-diisopropylethylamine were added untilthe pH was ≧8.0. The mixture was stirred at 20 to 30° C. for a minimumof 2 h until ≧99.0% conversion was obtained by HPLC analysis. Water (378L) was added while maintaining the temperature between 20 and 25° C. andstirred for 30 min. The phases were separated and the organic phase waswashed with a 10% w/w brine solution (38 kg NaCl in 340 kg of water).The phases were separated and the organic phase was dried with sodiumsulfate (5.4 kg) for a minimum of 30 min at 20 to 25° C. The mixture wasfiltered and the reactor that contained the sodium sulfate mixture wasrinsed with additional dichloromethane (27 L) and filtered.Dimethylformamide dimethylacetal (152 kg, 1276 mol) was added to thecombined filtrate over a minimum of 30 min while maintaining thetemperature between 20 and 30° C. The mixture was warmed to 37 to 42° C.and stirred for a minimum of 20 h until ≧99.0% conversion was obtainedby HPLC analysis. The reaction mixture was concentrated under vacuumusing a jacket temperature of 40 to 45° C. until 234 to 252 kg remainedin the reactor. MTBE (355 L) was added at 35 to 40° C. and the resultingmixture was concentrated under vacuum using a jacket temperature of 40to 45° C. until 414 to 432 kg remained in the reactor. The suspensionwas cooled to 20 to 25° C. over a minimum of 3 h and stirred for anadditional 2 h. The suspension was filtered and washed at 20 to 25° C.while stirring with MTBE (2×50 L) followed by acetone (2×101 L). The wetcake was dried under vacuum at 35 to 45° C. to provide 28.0 kg (83%yield) of 9. ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=8.2 Hz, 1H), 7.63(s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.42 (dd, J=6.96, 8.2 Hz, 1H), 6.94 (m,2H), 4.83 (d, J=12.9 Hz, 1H), 3.44 (d, J=12.9 Hz, 2H), 3.31 (s, 3H),3.22 (s, 6H); MS (ESI) m/z 373.2 (M+H⁺, 100%).

Step 4:4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid (Formula II)

Into a reactor was added 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3kg, 31.1 mol), 9 (5.27 kg, 14.1 mol) and methanol (63 L). The suspensionwas warmed to 50 to 55° C. and stirred for a minimum of 24 h until≧96.0% conversion was obtained by HPLC analysis. Methanol (10 L) andwater (37 L) were added while maintaining the temperature between 50 and55° C. The pH of the mixture was adjusted to 3.0 to 4.0 using 7% w/w HCl(prepared from 7.0 kg of concentrated HCl and 24 L of water) whilemaintaining the temperature between 50 and 55° C. The suspension wascooled to 20 to 25° C. over a minimum of 1 h and stirred for at least 60min. The resulting suspension was filtered and washed with water (2×26.3L) at 50 to 55° C. and methanol (2×10 L) at 20 to 25° C. The wet cakewas dried at 45 to 50° C. under vacuum to provide 5.85 kg (80% yield) ofFormula (II). ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.22 (s, 1H),8.72 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=2.4, 8.9Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s,2H), 3.82 (s, 6H); MS (ESI) m/z MS (ESI) m/z 517.2 (M−H⁺, 45%).

Step 5:

Method A: sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 2

Compound Formula (II) (130 g, 0.244 mol), absolute ethanol (975 mL, 7.5volumes) and water (715 mL, 5.5 volumes) were added to a reactor andwarmed to between 69 and 74° C. A 1.0 M sodium hydroxide solution inwater (260 ML, 2.0 volumes, 0.260 mol) was added dropwise whilemaintaining the temperature between 69 and 74° C. The pH of the reactionmixture was continuously monitored and the addition was stopped once thepH reached 9.5 to 10.5 (preferably 9.8 to 10). The mixture was stirredfor at least 1h at 69 to 74° C. and if the pH decreased from the definedrange then additional portions of the above 1.0 M NaOH solution wereadded until a pH of 9.5 to 10.5 was obtained. The reaction mixture waswarmed to an internal temperature of 72 to 77° C. The solution wasfiltered and transferred to a separate reactor while maintaining aninternal temperature of 69 to 77° C. Absolute ethanol (1690 mL, 13volumes) preheated to 69 to 74° C. was filtered and added to thereaction mixture while maintaining a reaction mixture temperature of 69to 74° C. Compound Formula (I) (1.30 g) was added and stirred for atleast 15 min at 62 to 67° C. and the reaction mixture was then heated to69 to 74° C. Seed crystals were present. The resulting suspension wasconcentrated at 60 to 74° C. under vacuum until 910 mL (7 volumes) ofsolvent were removed. Absolute ethanol (910 mL, 7 volumes) preheated to69 to 74° C. was filtered and added to the reaction mixture whilemaintaining a reaction mixture temperature of 69 to 74° C. The resultingsuspension was concentrated at 60 to 74° C. under vacuum until 910 mL (7volumes) of solvent were removed. The addition of 7 volumes of absoluteethanol followed by concentration as described above was repeated atleast four times. An In Process Control was obtained for % w/w of waterby KF analysis. The addition of 7 volumes of absolute ethanol followedby concentration was repeated until a KF of ≦15.0% w/w was reached. Thereaction mixture was cooled to 20 to 25° C. over a minimum of 2.5 to 3 hand stirred for at least 1 h at 20 to 25° C. and the suspension wasfiltered. The solid was washed twice with stirring using absoluteethanol (2×486.5 mL, 3.74 volumes). The wet cake was dried under vacuumat 40 to 45° C. until the residual ethanol content was ≦0.4% w/w asdetermined by GC analysis. A total of 96.8 g (71% yield) of compoundFormula (I) was obtained. ¹H NMR (300 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.61(s, 1H), 8.25 (d, J=7.6, 1H), 7.79 (dd, J=2.3, 8.8 Hz, 1H), 7.58 (s,1H), 7.40 (dd, J=8.2, 15.2 Hz, 1H), 7.25 (d, J=8.2, 1H), 7.17 (m, 2H),6.88 (s, 2H), 3.69 (s, 3H), 3.31 (s, 3H); MS (ESI) m/z 517.2 (M−H⁺,45%).

Method B: sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 1

To a stirred suspension of Compound Formula (II) (98.0 g, 190 mmol) inethanol (2.0 L) was added 1.044 M Sodium hydroxide in water (199 mL).The resultant homogeneous solution was stirred for 1 hour, during whichtime a thick precipitate formed. The product was collected byfiltration, and washed with ethanol (0.5 L) and diethyl ether (1.0 L).The resultant solid was dried in vacuo at 60-70° C. for 4 days toprovide 88.6 g (86.8%) of compound Formula (I) as a light tan solid, mp225° C. (decomp). ¹H NMR (DMSO-d₆) δ 9.86 (s, 1H), 8.60 (s, 1H), 8.29(d, 1H), 7.79 (dd, 1H), 7.60 (br s, 1H), 7.40 (dd, 1H), 7.29 (d, 1H),7.25-7.15 (m, 2H), 6.9 (br s, 2H), 4.9 (br s, 1H), 3.8 (br s, 1H), 3.70(s, 3H), 3.35 (br s, 3H); MS m/z 519 (M⁺−Na+H, 100%); CHN Anal. Calcd.for C₂₇H₁₉ClFN₄NaO₄0.33 EtOH1.3H₂O: C, 57.33; H, 4.10; N, 9.67. Found C,57.14; H, 3.99; N, 9.65.

Method C: amorphous sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate

1.0 g of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2 was dissolved in 350 mL of water at 65° C. The solution wasfrozen in a solid CO₂/acetone slurry and then freeze-dried. An amorphoushygroscopic, fluffy solid was obtained.

Example 4 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 4.

2.5 mL of ethanol was added to 50 mg of amorphous freeze-dried sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate(pre-dried for 1 hour under vacuum at 50° C.) in a screw-top vial. Thevial was shaken for 1 week with alternating 4 hour periods at 50° C. andambient temperature. Form 4 was isolated by filtration. XRPD data forForm 4 is shown in FIG. 7 and Table 3.

Example 5 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 6.

3.0 mL of methanol was added to 100 mg of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2 in a screw-top vial. The vial was shaken for 72 hours withalternating 4 hour periods at 50° C. and ambient temperature. Form 6 wasisolated by filtration. XRPD data for Form 6 is shown in FIG. 8 andTable 4; DSC data is shown in FIG. 9; TGA data is shown in FIG. 10; GVSdata is shown in FIG. 11.

Example 6 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 11.

3.0 mL of methanol was added to 100 mg of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2 in a screw-top vial. The vial was shaken for 72 hours withalternating 4 hour periods at 50° C. and ambient temperature. Theresulting slurry was filtered and the filtrate retained. 10 mL of theanti-solvent cyclohexane was added, but no precipitation occurred. Thesolution was allowed to evaporate to afford a mixture of Form 11 andForm 24. XRPD data for Form 11 is shown in FIG. 12 and Table 5; DSC datais shown in FIG. 13.

Example 7 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 12.

10 mL of 90% ethanol/10% water solution was added to 100 mg of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoateForm 2 in a screw-top vial. The vial was heated to 50° C. and shaken for2 hours. The resulting slurry was filtered at 50° C. and the filtrateretained. The filtrate was stored at 4° C. for 17 hours, but noprecipitation occurred. The vial was uncapped to allow evaporation toafford Form 12. XRPD data for Form 12 is shown in FIG. 14 and Table 6;DSC data is shown in FIG. 15; TGA data is shown in FIG. 16.

Example 8 Synthesis of sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoatepolymorph Form 24.

200 mg of 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid wasstirred in 4 mL of ethanol in a screw-top vial. 1.1 mol equivalents ofsodium hydroxide solution (406 μL, 1.044 M in water) were added. Thesolid dissolved followed by formation of a yellow precipitate. Thesample was a mixture of Form 4 and Form 24. The solid was washed with 10mL of ethanol and 20 mL of diethyl ether, and dried under vacuum at 70°C. for 2 days, and at 60° C. for a further 3 days to give Form 24. XRPDdata for Form 24 is shown in FIG. 17 and Table 7; DSC data is shown inFIG. 18; TGA data is shown in FIG. 19.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, these particular embodiments areto be considered as illustrative and not restrictive. It will beappreciated by one skilled in the art from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention, which is to be defined by theappended claims rather than by the specific embodiments.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

What is claimed is:
 1. A crystalline form of the compound of formula(I):

wherein the crystalline form is Form 4, characterized by an X-ray powderdiffraction pattern having peaks at 2θ angles of 13.27°, 22.96° and25.89°.
 2. The crystalline form of claim 1, characterized by an X-raypowder diffraction pattern substantially similar to FIG.
 7. 3. Acrystalline form of the compound of formula (I):

wherein the crystalline form is Form 6, characterized by at least one ofthe following features: an X-ray powder diffraction pattern having peaksat 2θ angles of 16.01°, 17.47°, 21.23° and 23.43°; a differentialscanning calorimetry (DSC) profile substantially similar to FIG. 9; athermal gravimetric analysis (TGA) profile substantially similar to FIG.10; and a gravimetric vapor sorption (GVS) profile substantially similarto FIG.
 11. 4. The crystalline form of claim 3, characterized by at anX-ray powder diffraction pattern having peaks at 2θ angles of 11.62°,16.01°, 17.47°, 21.23°, 23.43°, and 29.38°.
 5. The crystalline form ofclaim 3, characterized by an X-ray powder diffraction patternsubstantially similar to FIG.
 8. 6. The crystalline form of claim 3,characterized by at least two of the following features: an X-ray powderdiffraction pattern having peaks at 2θ angles of 16.01°, 17.47°, 21.23°and 23.43°; a differential scanning calorimetry (DSC) profilesubstantially similar to FIG. 9; a thermal gravimetric analysis (TGA)profile substantially similar to FIG. 10; and a gravimetric vaporsorption (GVS) profile substantially similar to FIG.
 11. 7. Acrystalline form of the compound of formula (I):

wherein the crystalline form is Form 11, characterized by at least oneof the following features: an X-ray powder diffraction pattern havingpeaks at 2θ angles of 13.03°, 26.21° and 27.08°; and a differentialscanning calorimetry (DSC) profile substantially similar to FIG.
 13. 8.The crystalline form of claim 7, characterized by an X-ray powderdiffraction pattern having peaks at 2θ angles of 13.03°, 15.72°, 25.66°,26.21°, and 27.08°.
 9. The crystalline form of claim 7, characterized byat least one an X-ray powder diffraction pattern substantially similarto FIG.
 12. 10. The crystalline form of claim 7, characterized by bothof the following features: an X-ray powder diffraction pattern havingpeaks at 2θ angles of 13.03°, 26.21° and 27.08°; and a differentialscanning calorimetry (DSC) profile substantially similar to FIG.
 13. 11.A crystalline form of the compound of formula (I):

wherein the crystalline form is Form 12, characterized by at least oneof the following features: an X-ray powder diffraction pattern havingpeaks at 2θ angles of 12.72°, 21.26°, 21.89°, and 25.57°; a differentialscanning calorimetry (DSC) profile substantially similar to FIG. 15; anda thermal gravimetric analysis (TGA) profile substantially similar toFIG.
 16. 12. The crystalline form of claim 11, characterized by an X-raypowder diffraction pattern having peaks at 2θ angles of 12.72°, 13.46°,21.26°, 21.89°, 25.57° , and 29.50°.
 13. The crystalline form of claim11, characterized by an X-ray powder diffraction pattern substantiallysimilar to FIG.
 14. 14. The crystalline form of claim 11, characterizedby at least two of the following features: an X-ray powder diffractionpattern having peaks at 2θ angles of 12.72°, 21.26°, 21.89°, and 25.57°; a differential scanning calorimetry (DSC) profile substantiallysimilar to FIG. 15; and a thermal gravimetric analysis (TGA) profilesubstantially similar to FIG.
 16. 15. A crystalline form of the compoundof formula (I):

wherein the crystalline form is Form 24, characterized by at least oneof the following features: an X-ray powder diffraction pattern havingpeaks at 2θ angles of 10.93°, 15.67°, 22.90°, 23.84°, and 26.91°; adifferential scanning calorimetry (DSC) profile substantially similar toFIG. 18; and a thermal gravimetric analysis (TGA) profile substantiallysimilar to FIG.
 19. 16. The crystalline form of claim 15, characterizedby an X-ray powder diffraction pattern having peaks at 2θ angles of10.93°, 15.67°,19.76°, 22.05°, 22.90°, 23.38°, 23.84° , and 26.91°. 17.The crystalline form of claim 15, characterized by an X-ray powderdiffraction pattern substantially similar to FIG.
 17. 18. Thecrystalline form of claim 15, characterized by at least two of thefollowing features: an X-ray powder diffraction pattern having peaks at2θ angles of 10.93°, 15.67°, 22.90°, 23.84° , and 26.91°; a differentialscanning calorimetry (DSC) profile substantially similar to FIG. 18; anda thermal gravimetric analysis (TGA) profile substantially similar toFIG.
 19. 19. A solid pharmaceutical composition comprising at least oneof the crystalline forms according to any one of claim 1, 3, 7, 11, or15, and at least one pharmaceutically acceptable carrier or diluent. 20.A method for treating cancer comprising the administration of atherapeutically effective amount of at least one of the crystallineforms according to any one of claim 1, 3, 7, 11, or 15, to a patient inneed thereof, wherein the cancer is selected from the group consistingof ovarian cancer, T-cell lymphoma and lung cancer.